The Plasmodium falciparum ABC transporter ABCI3 confers parasite strain-dependent pleiotropic antimalarial drug resistance.
The Plasmodium falciparum ABC transporter ABCI3 confers parasite strain-dependent pleiotropic antimalarial drug resistance.
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DOI：
10.1016/j.chembiol.2021.06.006
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发表时间：
2022-05-19
影响因子：
8.6
通讯作者：
Fidock DA
中科院分区：
文献类型：
--
作者：
Murithi JM;Deni I;Pasaje CFA;Okombo J;Bridgford JL;Gnädig NF;Edwards RL;Yeo T;Mok S;Burkhard AY;Coburn-Flynn O;Istvan ES;Sakata-Kato T;Gomez-Lorenzo MG;Cowell AN;Wicht KJ;Le Manach C;Kalantarov GF;Dey S;Duffey M;Laleu B;Lukens AK;Ottilie S;Vanaerschot M;Trakht IN;Gamo FJ;Wirth DF;Goldberg DE;Odom John AR;Chibale K;Winzeler EA;Niles JC;Fidock DA
恶性疟原虫对一线抗疟药物的广泛耐药性强调了开发具有新作用模式的化合物和确定新的可药用靶标的迫切需要。在这里，我们介绍了五种有效抑制恶性疟原虫无性血液阶段的化合物。通过基因编辑和条件性敲除证实的三种含甲酰胺化合物的抗性选择研究，将寄生虫转运蛋白ABCI 3中的点突变确定为抗性的主要介体。使用咪唑并吡啶或喹啉-甲酰胺化合物的选择研究也产生ABCI 3的变化，这次是通过基因扩增。咪唑吡啶的作用模式是由于抑制血红素解毒，证明了细胞积累和血红素分馏测定。对于拷贝数变异选择性咪唑并吡啶和喹啉-甲酰胺化合物，我们发现，表现为双相浓度-反应曲线的抗性可以独立地由氯喹抗性转运蛋白PfCRT中的突变介导。这些研究揭示了恶性疟原虫转运蛋白在克服不同寄生虫株的药物压力方面的相互联系。恶性疟原虫ABCI 3是抗疟原虫药物抗性的多效性介导物。菌株特异性抗性归因于abCI 3扩增或突变pfcrt。描述了ABCI 3，一种ATP结合盒转运蛋白，其传递恶性疟原虫对化学上不同的抗疟原虫化合物的抗性。体外抗性选择、基因编辑、药物敏感性、条件性敲除、药物细胞积累、蛋白定位和血红素分级分析将ABCI 3鉴定为抗性介体和推定的药物靶标。
Widespread Plasmodium falciparum resistance to first-line antimalarials underscores the vital need to develop compounds with novel modes of action and identify new druggable targets. Here, we profile five compounds that potently inhibit P. falciparum asexual blood stages. Resistance selection studies with three carboxamide-containing compounds, confirmed by gene editing and conditional knockdowns, identify point mutations in the parasite transporter ABCI3 as the primary mediator of resistance. Selection studies with imidazopyridine or quinoline-carboxamide compounds also yield changes in ABCI3, this time through gene amplification. Imidazopyridine mode of action is attributed to inhibition of heme detoxification, as evidenced by cellular accumulation and heme fractionation assays. For the copy-number variation-selecting imidazopyridine and quinoline-carboxamide compounds, we find that resistance, manifesting as a biphasic concentration-response curve, can independently be mediated by mutations in the chloroquine resistance transporter PfCRT. These studies reveal the interconnectedness of P. falciparum transporters in overcoming drug pressure in different parasite strains. P. falciparum ABCI3 is a pleiotropic mediator of antiplasmodial drug resistance Strain-specific resistance was attributed to abci3 amplification or mutant pfcrt Conditional knockdown assays identified ABCI3 as a putative drug target Murithi et al. describe ABCI3, an ATP-binding cassette transporter that conveys Plasmodium falciparum resistance to chemically diverse antiplasmodial compounds. In vitro resistance selections, gene editing, drug susceptibility, conditional knockdown, drug cellular accumulation, protein localization, and heme fractionation assays identified ABCI3 as both a resistance mediator and putative drug target.
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影响因子：
3.9
作者：
Egan, TJ;Mavuso, WW;Marques, HM
通讯作者：
Marques, HM
影响因子：
14.9
作者：
Deitsch, KW;Driskill, CL;Wellems, TE
通讯作者：
Wellems, TE
DOI：
10.1073/pnas.0711067105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Elliott, David A.;McIntosh, Michael T.;Joiner, Keith A.
通讯作者：
Joiner, Keith A.
影响因子：
16.6
作者：
Baker DA;Stewart LB;Large JM;Bowyer PW;Ansell KH;Jiménez-Díaz MB;El Bakkouri M;Birchall K;Dechering KJ;Bouloc NS;Coombs PJ;Whalley D;Harding DJ;Smiljanic-Hurley E;Wheldon MC;Walker EM;Dessens JT;Lafuente MJ;Sanz LM;Gamo FJ;Ferrer SB;Hui R;Bousema T;Angulo-Barturén I;Merritt AT;Croft SL;Gutteridge WE;Kettleborough CA;Osborne SA
通讯作者：
Osborne SA
影响因子：
4.6
作者：
Dorjsuren D;Eastman RT;Wicht KJ;Jansen D;Talley DC;Sigmon BA;Zakharov AV;Roncal N;Girvin AT;Antonova-Koch Y;Will PM;Shah P;Sun H;Klumpp-Thomas C;Mok S;Yeo T;Meister S;Marugan JJ;Ross LS;Xu X;Maloney DJ;Jadhav A;Mott BT;Sciotti RJ;Winzeler EA;Waters NC;Campbell RF;Huang W;Simeonov A;Fidock DA
通讯作者：
Fidock DA